Purpose Men with localized prostate cancer often are treated with external radiotherapy (RT) over 8 to 9 weeks. Hypofractionated RT is given over a shorter time with larger doses per treatment than ...standard RT. We hypothesized that hypofractionation versus conventional fractionation is similar in efficacy without increased toxicity. Patients and Methods We conducted a multicenter randomized noninferiority trial in intermediate-risk prostate cancer (T1 to 2a, Gleason score ≤ 6, and prostate-specific antigen PSA 10.1 to 20 ng/mL; T2b to 2c, Gleason ≤ 6, and PSA ≤ 20 ng/mL; or T1 to 2, Gleason = 7, and PSA ≤ 20 ng/mL). Patients were allocated to conventional RT of 78 Gy in 39 fractions over 8 weeks or to hypofractionated RT of 60 Gy in 20 fractions over 4 weeks. Androgen deprivation was not permitted with therapy. The primary outcome was biochemical-clinical failure (BCF) defined by any of the following: PSA failure (nadir + 2), hormonal intervention, clinical local or distant failure, or death as a result of prostate cancer. The noninferiority margin was 7.5% (hazard ratio, < 1.32). Results Median follow-up was 6.0 years. One hundred nine of 608 patients in the hypofractionated arm versus 117 of 598 in the standard arm experienced BCF. Most of the events were PSA failures. The 5-year BCF disease-free survival was 85% in both arms (hazard ratio short v standard, 0.96; 90% CI, 0.77 to 1.2). Ten deaths as a result of prostate cancer occurred in the short arm and 12 in the standard arm. No significant differences were detected between arms for grade ≥ 3 late genitourinary and GI toxicity. Conclusion The hypofractionated RT regimen used in this trial was not inferior to conventional RT and was not associated with increased late toxicity. Hypofractionated RT is more convenient for patients and should be considered for intermediate-risk prostate cancer.
Abstract
The Astropy Project supports and fosters the development of open-source and openly developed
Python
packages that provide commonly needed functionality to the astronomical community. A key ...element of the Astropy Project is the core package
astropy
, which serves as the foundation for more specialized projects and packages. In this article, we summarize key features in the core package as of the recent major release, version 5.0, and provide major updates on the Project. We then discuss supporting a broader ecosystem of interoperable packages, including connections with several astronomical observatories and missions. We also revisit the future outlook of the Astropy Project and the current status of Learn Astropy. We conclude by raising and discussing the current and future challenges facing the Project.
SARS-CoV-2 has caused a global pandemic, and has taken over 1.7 million lives as of mid-December, 2020. Although great progress has been made in the development of effective countermeasures, with ...several pharmaceutical companies approved or poised to deliver vaccines to market, there is still an unmet need of essential antiviral drugs with therapeutic impact for the treatment of moderate-to-severe COVID-19. Towards this goal, a high-throughput assay was used to screen SARS-CoV-2 nsp15 uracil-dependent endonuclease (endoU) function against 13 thousand compounds from drug and lead repurposing compound libraries. While over 80% of initial hit compounds were pan-assay inhibitory compounds, three hits were confirmed as nsp15 endoU inhibitors in the 1-20 μM range in vitro. Furthermore, Exebryl-1, a ß-amyloid anti-aggregation molecule for Alzheimer's therapy, was shown to have antiviral activity between 10 to 66 μM, in Vero 76, Caco-2, and Calu-3 cells. Although the inhibitory concentrations determined for Exebryl-1 exceed those recommended for therapeutic intervention, our findings show great promise for further optimization of Exebryl-1 as an nsp15 endoU inhibitor and as a SARS-CoV-2 antiviral.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although missing data methods have advanced in recent years, methodologists have devoted less attention to multilevel data structures where observations at level-1 are nested within higher-order ...organizational units at level-2 (e.g., individuals within neighborhoods; repeated measures nested within individuals; students nested within classrooms). Joint modeling and chained equations imputation are the principal imputation frameworks for single-level data, and both have multilevel counterparts. These approaches differ algorithmically and in their functionality; both are appropriate for simple random intercept analyses with normally distributed data, but they differ beyond that. The purpose of this paper is to describe multilevel imputation strategies and evaluate their performance in a variety of common analysis models. Using multiple imputation theory and computer simulations, we derive 4 major conclusions: (a) joint modeling and chained equations imputation are appropriate for random intercept analyses; (b) the joint model is superior for analyses that posit different within- and between-cluster associations (e.g., a multilevel regression model that includes a level-1 predictor and its cluster means, a multilevel structural equation model with different path values at level-1 and level-2); (c) chained equations imputation provides a dramatic improvement over joint modeling in random slope analyses; and (d) a latent variable formulation for categorical variables is quite effective. We use a real data analysis to demonstrate multilevel imputation, and we suggest a number of avenues for future research.
Drug-eluting balloons (DEB) may reduce infrapopliteal restenosis and reintervention rates versus percutaneous transluminal angioplasty (PTA) and improve wound healing/limb preservation.
The goal of ...this clinical trial was to assess the efficacy and safety of IN.PACT Amphirion drug-eluting balloons (IA-DEB) compared to PTA for infrapopliteal arterial revascularization in patients with critical limb ischemia (CLI).
Within a prospective, multicenter, randomized, controlled trial with independent clinical event adjudication and angiographic and wound core laboratories 358 CLI patients were randomized 2:1 to IA-DEB or PTA. The 2 coprimary efficacy endpoints through 12 months were clinically driven target lesion revascularization (CD-TLR) and late lumen loss (LLL). The primary safety endpoint through 6 months was a composite of all-cause mortality, major amputation, and CD-TLR.
Clinical characteristics were similar between the 2 groups. Significant baseline differences between the IA-DEB and PTA arms included mean lesion length (10.2 cm vs. 12.9 cm; p = 0.002), impaired inflow (40.7% vs. 28.8%; p = 0.035), and previous target limb revascularization (32.2% vs. 21.8%; p = 0.047). Primary efficacy results of IA-DEB versus PTA were CD-TLR of 9.2% versus 13.1% (p = 0.291) and LLL of 0.61 ± 0.78 mm versus 0.62 ± 0.78 mm (p = 0.950). Primary safety endpoints were 17.7% versus 15.8% (p = 0.021) and met the noninferiority hypothesis. A safety signal driven by major amputations through 12 months was observed in the IA-DEB arm versus the PTA arm (8.8% vs. 3.6%; p = 0.080).
In patients with CLI, IA-DEB had comparable efficacy to PTA. While primary safety was met, there was a trend towards an increased major amputation rate through 12 months compared to PTA. (Study of IN.PACT Amphirion™ Drug Eluting Balloon vs. Standard PTA for the Treatment of Below the Knee Critical Limb Ischemia INPACT-DEEP; NCT00941733).
Atomistic molecular dynamics simulations were performed to study hydrated Nafion systems large enough (∼2 million atoms, ∼30 nm box length) to directly observe several hydrophilic domains at the ...molecular level. These systems consisted of six of the most significant and relevant morphological models of Nafion to-date: (1) the cluster−channel model, (2) the parallel cylinder model, (3) the local order model, (4) the lamellar model, (5) the rod network model, and (6) a “random” model that does not directly assume any particular geometry, distribution, or morphology. Each system was initially built to closely approximate the proposed hydrophilic cluster structure in a given model. Molecular dynamics simulations were then used to observe resulting changes from and behavior of the assumed initial configurations. These simulations revealed fast intercluster “bridge” formation and network percolation in all models. Sulfonate groups were found inside these bridges and played a significant role in percolation. Sulfonates also strongly aggregated around and inside clusters. Cluster surfaces were analyzed to study the hydrophilic−hydrophobic interface. Interfacial area and cluster volume significantly increased during the simulations, and radial distribution functions and structure factors were also calculated. All nonrandom models clearly exhibited the characteristic experimental scattering peak, underscoring the insensitivity of this measurement to hydrophilic domain structure and highlighting the need for future work to clearly distinguish morphological models of Nafion.
Lymphoma is the most common hematopoietic tumour in dogs and is remarkably similar to the human disease. Tumour biomarker discovery is providing new tools for diagnostics and predicting therapeutic ...response and clinical outcome. MicroRNAs are small non-coding RNAs that participate in post-transcriptional gene regulation and their aberrant expression can impact genes involved in cancer. The aim of this study was to characterize microRNA expression in lymph nodes and plasma from dogs with multicentric B or T cell lymphoma compared to healthy control dogs. We further compared expression between lymph nodes and corresponding plasma samples and assessed changes in expression at relapse compared to time of diagnosis. Lastly, we investigated microRNAs for association with clinical outcome in patients treated with CHOP chemotherapy. A customized PCR array was utilized to profile 38 canine target microRNAs. Quantification was performed using real time RT-qPCR and relative expression was determined by the delta-delta Ct method. In lymph nodes, there were 16 microRNAs with significantly altered expression for B cell lymphoma and 9 for T cell lymphoma. In plasma, there were 15 microRNAs altered for B cell lymphoma and 3 for T cell lymphoma. The majority of microRNAs did not have correlated expression between lymph node and plasma and only 8 microRNAs were significantly different between diagnosis and relapse. For B cell lymphoma, 8 microRNAs had differential expression in the non-remission group compared to dogs that completed CHOP in complete remission. Four of these microRNAs were also altered in patients that died prior to one-year. Kaplan-Meier survival curves for high versus low microRNA expression revealed that 10 microRNAs were correlated with progression-free survival and 3 with overall survival. This study highlights microRNAs of interest for canine multicentric lymphoma. Future goals include development of microRNA panels that may be useful as biomarkers with the intent to provide improved outcome prediction to veterinary cancer patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The role of law in adaptive governance Cosens, Barbara A.; Craig, Robin K.; Hirsch, Shana Lee ...
Ecology and society,
03/2017, Letnik:
22, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The term “governance” encompasses both governmental and nongovernmental participation in collective choice and action. Law dictates the structure, boundaries, rules, and processes within which ...governmental action takes place, and in doing so becomes one of the focal points for analysis of barriers to adaptation as the effects of climate change are felt. Adaptive governance must therefore contemplate a level of flexibility and evolution in governmental action beyond that currently found in the heavily administrative governments of many democracies. Nevertheless, over time, law itself has proven highly adaptive in western systems of government, evolving to address and even facilitate the emergence of new social norms (such as the rights of women and minorities) or to provide remedies for emerging problems (such as pollution). Thus, there is no question that law can adapt, evolve, and be reformed to make room for adaptive governance. In doing this, not only may barriers be removed, but law may be adjusted to facilitate adaptive governance and to aid in institutionalizing new and emerging approaches to governance. The key is to do so in a way that also enhances legitimacy, accountability, and justice, or else such reforms will never be adopted by democratic societies, or if adopted, will destabilize those societies. By identifying those aspects of the frameworks for adaptive governance reviewed in the introduction to this special feature relevant to the legal system, we present guidelines for evaluating the role of law in environmental governance to identify the ways in which law can be used, adapted, and reformed to facilitate adaptive governance and to do so in a way that enhances the legitimacy of governmental action.
Objectives
There is inconsistent evidence on the influence of ethnicity on duration of untreated psychosis (DUP). We investigated ethnic differences in DUP in a large epidemiological dataset of first ...episode psychosis patients in an inner city area of south London, UK.
Methods
We analysed data on 558 first episode psychosis patients at the South London and Maudsley NHS Trust, between 2010 and 2012. We performed multivariable logistic regression to estimate the odds of a short DUP (≤ 6 months) by ethnic group, controlling for confounders.
Results
There was no evidence that ethnicity is associated with duration of untreated psychosis. However, we found evidence that a short DUP was strongly associated with age, living circumstances, and pathways to care variables (involuntary admission, out of office hour contact, accident and emergency referral, criminal justice agency referral and family involvement in help-seeking). Conversely, a long DUP was associated with report of social isolation, living alone, being single and General Practitioner referral.
Conclusion
Our findings suggest that indicators of social isolation were associated with long DUP. Our data also show that pathways into care characteristics play significant role in DUP. Thus, the challenge of tackling the issue of timely access to EI under the new Access and Waiting Time standard for psychosis requires a multilevel approach, including joint working with communities, public awareness of psychosis, less restrictive referral pathways and adequate resourcing of early intervention for psychosis services. These will go a long way in addressing patients’ needs rather than be determined by service structures.
PDF
